Demand for medically assisted reproduction (MAR) continues to increase, in part due to the widening availability of treatments such as in vitro fertilisation (IVF), and also due to the increasing prevalence of fertility issues that act as a barrier to reproduction.
The IVF process involves in vitro fertilisation of one or more pre-obtained eggs (ova) before embryo(s), ultimately formed thereby, are transferred (back) into a uterus to allow embryonic implantation to occur. Typically, the IVF process is preceded by monitoring and stimulation of the ovulatory process before an ovum (or more typically several ova) is removed from the ovaries. The extracted ovum is then contacted with sperm in a fluid medium in a laboratory to facilitate fertilisation. The fertilised ovum (zygote) is then cultured for several days in an appropriate growth medium to form an embryo(s), before the embryo(s) are finally transferred (back) to a uterus. Pregnancy may then be established following successful implantation of the embryo(s) into the uterus.
The success of MAR techniques such as IVF depends on a complex array of factors, some of which can be readily controlled whilst others cannot. Often, multiple embryos (formed via IVF) are transferred to a uterus in order to improve the overall success rate of the IVF treatment, especially where fertility issues are particularly pronounced. In particular, impregnating a uterus with multiple embryos decreases the likelihood of complete embryonic implantation failure, since the probability that at least one of the embryos will become successfully implanted within the uterus is increased. However, such a strategy carries inherant risks, since multiple implantations can lead to multiple pregnancies/multiple births, which affords well known dangers. As such, there have been various advances in the field of medically assisted reproduction to improve implantation rates, not least to reduce multiple embryo transfers and the consequential risks arising therefrom. For example, luteal support is provided via the administration of medication, such as progesterone, progestins or GnRH agonists, to increase the success rate of implantation and early embryogenesis. However, implantation rates are often still too low to completely dispense with multiple embryo transfers.
The implantation of the human embryo into the uterus is a complex mechanism, which involves both the embryo, and the endometrial epithelium. The phases of apposition, adhesion and invasion involves a multiplicity of molecules, which play an unique role in the process, the molecular dialogue between the conceived and the endometrium implies interactions among cells, and between cells and biochemical factors. These mechanisms, if suitably expressed or inhibited, are of help to determine the receptivity or non-receptivity state of the endometrium versus the embryo.
Embryonic implantation and relevant mechanisms are described in some detail in WO 2013/178587 (MAXIA et al), especially page 1, line 6 to page 6, line 17 thereof, which is hereby incorporated by reference.
Despite the advanced state of MAR technologies in the present day, embryonic implantation failure still remains an unsettled problem and is considered a principle reason for infertility in healthy women. Implantation success rates, using MAR, tend to be about 25%. Inadequate uterine receptivity is therefore deemed to be responsible for approximately two thirds of all failures (for one third the embryo is considered as being responsible).
WO 2013/178587 (MAXIA et al), which is hereby incorporated by reference, discloses recent advances stemming from the recognition of melatonin's key role in the embryonic nesting process. MAXIA et al, describes the use of melatonin (and/or analogs thereof) to promote embryonic implantation and/or mitigate against embryonic implantation failure, especially in mammalian subjects suffering from infertility or polyabortion. In particular, MAXIA et al describes melatonin-containing topical uterine washing/endometrial washing compositions which may be advantageously topically administered within the uterus at the time of or after oocyte retrieval, though suitably several days before embryonic transfer to said uterus. Such washings were shown to dramatically improve implantation success rates and consequential pregnancy rates.
However, there remains a need to optimise topical melatonin formulations for MAR treatments, and in particular address formulation stability issues (for all stages of its production, storage, shipping and use) without compromising (or with minimal compromises in respect of) formulation efficacy; clinical safety; manufacturing viability, consistency, cost, and quality control. The development of such optimised formulations is a significant challenge in view of the delicate balance and interplay between the respective components of such formulations. As such, significant research and development was undertaken by the present applicants to develop alternative and/or improved liquid formulations of melatonin. Desirably, any new such formulations would solve at least one problem inherent in the prior art.